- Email: [email protected]
A review of recently described genetic alterations in central nervous system tumors
Journal Pre-proof A review of recently described genetic alterations in central nervous system tumors
Calixto-Hope G. Lucas, David A. Solomon, Arie Perry PII:
S0046-8177(19)30191-1
DOI:
https://doi.org/10.1016/j.humpath.2019.10.009
Reference:
YHUPA 4939
To appear in:
Human Pathology
Received date:
21 October 2019
Accepted date:
24 October 2019
Please cite this article as: C.-H.G. Lucas, D.A. Solomon and A. Perry, A review of recently described genetic alterations in central nervous system tumors, Human Pathology(2019), https://doi.org/10.1016/j.humpath.2019.10.009
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof A Review of Recently Described Genetic Alterations in Central Nervous System Tumors Calixto-Hope G. Lucas1, David A. Solomon1,2 Arie Perry1,3
ro
Corresponding author: Arie Perry, MD Department of Pathology, Division of Neuropathology University of California, San Francisco 505 Parnassus Avenue, Room M551 San Francisco, California 94143 Phone: (415) 476 - 5236 Email: [email protected]
of
1. Department of Pathology, University of California, San Francisco, CA, USA 2. Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA 3. Department of Neurological Surgery, University of California, San Francisco, CA, USA
re
-p
Key words: CNS tumors, molecular neuropathology, targeted next-generation sequencing, multinodular vacuolating neuronal tumor, chordoid glioma, pineal parenchymal tumor, extraventricular neurocytoma, polymorphous low grade neuroepithelial tumor of the young, myxoid glioneuronal tumor, CNS embryonal tumors, BCOR, FOXR2, CIC, MN1
Jo
ur
na
lP
This manuscript has not been previously published or submitted elsewhere for review. The authors declare no conflicts of interest. D.A.S is supported by NIH Director’s Early Independence Award (DP5 OD021403).
Journal Pre-proof INTRODUCTION
Advances in molecular profiling of central nervous system tumors have enabled the development of classification schemes with improved diagnostic and prognostic accuracy. As such, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) introduced a paradigm shift in the diagnosis of brain tumors [1]. For instance, integrated
of
assessment incorporating both histologic features and genetic alterations was introduced into the
ro
diagnostic framework of gliomas. IDH1/2 mutation status now represents the most important
-p
initial stratifier of diffuse gliomas in adults, although rarer subtypes within the IDH-wildtype
re
category continue to be elucidated. Medulloblastomas and other embryonal neoplasms were also genetically defined and segregated based on molecular subtypes, and one molecular subtype of
lP
ependymoma was added. In this review, we summarize the rapidly evolving spectrum of
na
recurrent genetic alterations described in central nervous system tumor entities since the
ur
publication of the WHO 2016.
Jo
PREVIOUSLY RECOGNIZED ENTITIES WITH NEWLY DESCRIBED GENETIC ALTERATIONS
Multinodular and vacuolating neuronal tumor Multinodular and vacuolating neuronal tumor of the cerebrum (MVNT) is a low-grade neuronal neoplasm of the cerebral hemispheres recently added to the WHO 2016 as a potential subtype of gangliocytoma/ganglioglioma or other glioneuronal neoplasm. Histologically, the tumor is composed of nodules of small- to medium-sized neuronal cells with prominent intracytoplasmic
1
Journal Pre-proof and stromal vacuoles (Fig. 1). Tumors are commonly located in the deep cortex and subcortical white matter of the temporal lobe. As such, patients typically present with seizures. Given the limited literature at publication, the WHO 2016 did not delineate whether MVNT is a neoplastic or hamartomatous process. Some targeted next-generation sequencing studies failed to find any recurrent mutations in genes commonly altered in other low-grade brain tumors (mTOR pathway genes, BRAF, FGFR1, or MYB), potentially indicating that MVNT could be malformative [2,3].
of
However, in a series by Pekmezci et al, recurrent and mutually exclusive mutations in MAP2K1
ro
and BRAF were identified [4]. Out of eight sequenced tumors, five demonstrated missense
-p
mutations or small in-frame deletions within exon 2 of the MAP2K1 gene, two cases
re
demonstrated mutations other than the more common p.V600E variant in the BRAF gene, and one case demonstrated an FGFR2-INA in-frame gene fusion. These findings confirm that MVNT
lP
is a clonal neoplasm characterized by solitary pathogenic alterations that cause activation of the
ur
Chordoid glioma
na
Ras-Raf-MAP kinase signaling pathway.
Jo
Chordoid glioma of the third ventricle (WHO grade II) is a rare, slow-growing, non-invasive glial tumor. Histologically, the tumor exhibits chordoma-like clusters and cords of epithelioid tumors cells embedded within a mucinous stroma and often surrounded by a lymphoplasmacyterich inflammatory infiltrate (Fig. 2). They typically occur in adults and present with obstructive symptoms or endocrine abnormalities. Due to their location in the anterior third ventricle, gross total resection is often challenging, with tumor progression and even patient death being relatively common despite slow growth rates. No recurrent genetic abnormalities were described prior to 2016, but two recently published series have demonstrated a signature PRKCA mutation.
2
Journal Pre-proof In a series of 13 chordoid gliomas, Goode et al identified a recurrent p.D463H missense mutation in PRKCA in all 13 tumors [5]. In a concurrently published series of 16 chordoid gliomas, Rosenberg et al demonstrated the identical p.D463H missense mutation in PRKCA in 15 tumors [6]. The missense mutation localizes within the active site of the kinase domain of the encoded protein kinase C alpha and has not been reported in any other tumor type to date. Together, these studies identify PRKCA p.D463H as a recurrent and specific oncogenic mutation in chordoid
ro
of
gliomas, also providing a potential therapeutic target for further treatment after surgery.
-p
Pineal parenchymal tumors
re
Pineal parenchymal tumors consist of a spectrum of neoplasms that arise from the specialized neuronal cells of the pineal gland and include pineocytoma (WHO grade I), pineal parenchymal
lP
tumor of intermediate differentiation (WHO grade II or III), and pineoblastoma (WHO grade
na
IV). All of them stain diffusely with synaptophysin, while neurofilament expression is roughly inversely proportional to grade.
ur
Pineoblastoma is a rare, malignant embryonal neoplasm of the pineal gland that usually occurs in
Jo
children and young adults. The tumor is composed of sheets of small immature neuroepithelial cells with frequent mitoses. Occasional areas with Homer Wright and Flexner-Wintersteiner rosettes may be seen (Fig. 3A). Genetically, associations with hereditary retinoblastoma (socalled “trilateral retinoblastoma”) and familial adenomatous polyposis have been reported [7,8]. A portion of pineoblastomas develop in patients with germline and/or somatic DICER1 mutations [9]. A recent publication has also demonstrated recurrent homozygous deletions of DROSHA in pineoblastoma. In a series of 19 sequenced sporadic pineoblastomas, homozygous deletion of DROSHA was identified in five cases [10]. DROSHA is involved in miRNA
3
Journal Pre-proof processing in the nucleus, upstream of DICER1 [11]. Another recent series of four pineoblastomas by Lee et al showed somatic DICER1 mutations in two tumors and homozygous deletion of DROSHA in the other two tumors [12]. Together, these data implicate dysregulation of miRNA processing as a central theme in the pathogenesis of pineoblastoma. Pineal parenchymal tumors of intermediate differentiation (PPTID) are tumors of the pineal gland with biologic behavior that is better than pineoblastoma but worse than pineocytoma. They
of
can be composed of sheets or lobules of uniform round cells with mild to moderate atypia and
ro
mitotic figures, but they otherwise lack the primitive (hyperchromatic nuclei, nuclear molding,
-p
cell wrapping, etc.) appearance of pineoblastoma (Fig. 3B). In contrast to pineoblastomas,
re
PPTIDs have not been found to have DICER1 or DROSHA alterations. Instead, the series of by Lee et al demonstrated an in-frame insertion (p.R313delinsPRR) in the KBTBD4 gene in all three
lP
PPTIDs examined [12]. As such, these mutations may be diagnostically useful in distinguishing
na
pineoblastoma and pineal parenchymal tumors of intermediate differentiation from one another, although larger studies are still needed to more fully elucidate the genetic spectrum.
ur
To date, no signature genetic alterations have been reported in the literature for pineocytoma,
Jo
which features a more mature appearance including a ‘salt and pepper’ chromatin pattern, low mitotic index, and prominent pineocytic rosettes.
Extraventricular neurocytoma Extraventricular neurocytoma (WHO grade II) is a rare neuronal neoplasm that can present throughout the central nervous system parenchyma, but otherwise resembles the central neurocytoma encountered within the lateral ventricles. Tumors are histologically heterogeneous but display a mostly solid growth pattern and are composed of small, uniform round
4
Journal Pre-proof oligodendrocyte-like or neurocyte-like cells (i.e. small mature neurons), often with perinuclear clear haloes; neuronal differentiation is evident in the form of neuropil formation, neurocytic rosettes (with central neuropil similar in appearance to pineocytic rosettes), and diffuse synaptophysin immunoreactivity (Fig. 4). Other common features include limited ganglion cell differentiation, hyalinized vessels, and calcifications. Co-deletion of chromosome arms 1p and 19q and mutations of IDH1 or IDH2 mutation are absent by definition, thereby excluding the
of
alternate diagnostic consideration of oligodendroglioma with extensive neurocytic differentiation
ro
[13]. No genomic studies had been performed prior to the WHO 2016 scheme. However, a recent
-p
series of 15 sequenced extraventricular neurocytomas by Sievers et al demonstrated frequent
re
FGFR family alterations. They found FGFR gene rearrangements in 11 tumors, eight showing FGFR1-TACC1 fusion, one with FGFR1-EVI5 fusion, and the remaining two with FGFR3-
lP
TACC3 fusion [14]. FGFR fusions are thought to drive enhanced downstream signaling through
na
MAP kinase pathway effectors by way of homodimerization and autophosphorylation mediated by coiled coil domains resident in their respective fusion partners [15,16]. Although first
ur
described in glioblastoma, FGFR-TACC gene fusions have also been described in low-grade
Jo
brain tumors, including dysembryoplastic neuroepithelial tumor (DNT) [17], pediatric-type IDHwildtype oligodendroglioma [18], and rosette-forming glioneuronal tumor (RGNT) [19], albeit not at the higher frequency reported in the extraventricular neurocytoma series. Tumorigenic drivers, including FGFR gene alterations, have not been reported in central neurocytoma to date.
NEWLY PROPOSED ENTITIES WITH SIGNATURE MOLECULAR ALTERATIONS
Polymorphous low grade neuroepithelial tumor of the young
5
Journal Pre-proof Polymorphous low grade neuroepithelial tumor of the young (PLNTY) is a recently proposed morphologically and molecularly distinct tumor entity within the spectrum of low-grade epilepsy-associated glioneuronal tumors. Microscopic findings include an infiltrative, often heavily calcified oligodendroglioma-like neoplasm, but with variable neuronal features and a hallmark immunohistochemical finding of intense immunolabeling for CD34 (Fig. 5). Molecular profiling of a series of PLNTYs has shown frequent genetic alterations in BRAF and FGFR
of
family genes. In a series of eight PLNTY tumors published by Huse et al, three tumors harbored
ro
BRAFV600E mutations while another four had various FGFR family alterations. Of the four
-p
tumors with FGFR alterations, one showed an FGFR3-TACC3 fusion, one showed an FGFR2-
re
CTNNA3 fusion, and two showed FGFR2-KIAA1598 fusions [20]. As mentioned previously, FGFR fusions are thought to upregulate signaling and activation of the downstream MAP kinase
lP
pathways; these alterations are not specific to PLNTY. Similarly, MAP kinase activation through
na
BRAFV600E mutation has been implicated in numerous other low-grade epileptogenic tumors including gangliogliomas and pleomorphic xanthoastrocytomas [21]. The cases reported to date
ur
have followed benign clinical courses. While not characterized by any one signature genetical
Jo
alteration, the unique combined morphologic, immunohistochemical, and molecular profile of these tumors suggest that PLNTY represents a distinct biological entity.
Myxoid glioneuronal tumor Myxoid glioneuronal tumor is a newly proposed tumor entity that arises in the septum pellucidum, corpus callosum, or periventricular white matter and harbors a unique genetic alteration. These tumors usually show a columnar arrangement of oligodendroglial-like cells in a mucin-rich stroma with “floating” ganglion cells, reminiscent of DNT (Fig. 6). However, they
6
Journal Pre-proof lack the multinodular architecture with mucin-rich patterned nodules typical of cortically-based DNT. A subset also features neurocytic rosettes, similar to rosette-forming glioneuronal tumor (RGNT). These DNT- and RGNT-like neoplasms arising in the septum pellucidum have been described previously, but comprehensive molecular characterization has only recently been performed with multiple series showing that these myxoid glioneuronal tumors possess a specific and recurrent mutation in PDGFRA. In a series by Solomon et al, all four sequenced cases of
of
myxoid glioneuronal tumor showed dinucleotide substitutions in the PDGFRA gene, three with
ro
p.K385L and one with p.K385I. The dinucleotide substitution resides within the region encoding
-p
extracellular immunoglobulin-like C2-type domain 4 [22]. Some of the above described myxoid
re
glioneuronal tumors demonstrated intraventricular dissemination but otherwise exhibited benign behavior [23]. In a series of similar tumors involving the septum pellucidum by Chiang et al, 13
lP
of 18 cases showed the identical PDGFRA dinucleotide mutations [24]. Of 14 tumors with
na
PDGFRA mutations, 11 had p.K385L and 2 had p.K385I, whereas one other had p.E365insKW insertion. Three of the four tumors without PDGFRA mutations had FGFR1 alterations and the
ur
remaining tumor had an NF1 mutation, suggesting that they may have been pilocytic
Jo
astrocytomas instead. PDGFRA mutations have been reported in high-grade diffuse gliomas but occur invariably in conjunction with other pathogenic alterations such as TERT promoter mutation, CDKN2A homozygous deletion, or mutation in H3F3A or HIST1H3B [25,26]. To date, PDGFRA mutations have not been identified as the solitary genetic driver in any central nervous system tumors, including cortically-based DNT. The findings therefore argue that myxoid glioneuronal tumor is a distinct tumor entity.
Central nervous system embryonal tumors
7
Journal Pre-proof Previously classified as “primitive neuroectodermal tumors” (PNETs), central nervous system (CNS) embryonal tumors represent a biologically heterogenous group of highly malignant “small round cell” tumors with variable evidence of neuronal, astrocytic, myogenic, and/or melanocytic differentiation. Various genetic alterations have been described that are used to define the different subtypes. These include C19MC amplification in embryonal tumor with multilayered rosettes (added as an entity in the WHO 2016) and either SMARCB1 or SMARCA4 biallelic
of
inactivation in atypical teratoid/rhabdoid tumor [1]. However, other central nervous system
ro
embryonal tumors lacking distinctive histologic or genetic features remain diagnostically
-p
challenging.
re
Comprehensive genetic analysis by Sturm et al of a large cohort of tumors previously classified as CNS PNETs revealed that most could be reclassified as other well-established entities when
lP
studied genomically; however, several new and distinct molecular subgroups emerged. Of 323
na
tumors studied by DNA methylation profiling, 36 were reclassified as embryonal tumor with multilayered rosettes, 15 as supratentorial ependymomas, 14 as atypical teratoid/rhabdoid
ur
tumors, and 10 as H3 K27M-mutant diffuse midline gliomas, among others. In contrast, 77
Jo
formed four distinct methylation groups with unique genetic alterations that did not overlap with any previously known central nervous system tumor entities and as such, new entities were proposed [27].
High-grade neuroepithelial tumor with BCOR internal tandem duplication One group of ten tumors from the Sturm series is termed “high-grade neuroepithelial tumor (HGNET) with BCOR internal tandem duplication”. These tumors presented within the first year of life and occurred throughout the neuraxis. Histologically, in addition to primitive features, the
8
Journal Pre-proof tumors showed some overlapping features with glioblastoma and ependymoma, including solid growth, oval to tapered nuclei, variably fibrillar processes, perivascular pseudorosettes (albeit often GFAP negative), and areas of palisading necrosis (Fig. 7A-B). This entity shows robust upregulation of BCOR and activation of the WNT pathway that can be detected by nuclear immunostaining for BCOR (Fig. 7C) and beta-catenin respectively [28]. This entity often leads to death within a few months of diagnosis, although occasional long-term survivors have been
of
described [29,30]. This tumor entity is genetically defined by an internal tandem duplication
ro
within exon 15 of the BCOR transcriptional corepressor gene [29,31]. The same alteration has
-p
been described in other tumor types outside of the central nervous system, including clear cell
re
sarcoma of the kidney and primitive myxoid mesenchymal tumor of [32,33]. In a series by Ferris et al, the BCOR exon 15 internal tandem duplication (ex15 ITD) was the solitary pathogenic
lP
alteration identified in six of ten cases; The remaining four cases showed various additional
na
pathogenic alterations including CDKN2A/B homozygous deletion, TERT amplification or promotor hotspot mutation, or damaging mutations in TP53, BCORL1, EP300, SMARCA2, and
ur
STAG2 [30]. They also suggested the more specific nomenclature of HGNET with BCOR exon
Jo
15 ITD for this tumor entity, since a wide range of other CNS tumor types harbor BCOR alterations other than the exon 15 ITD.
CNS neuroblastoma with FOXR2 activation A separate group of 44 tumors in the Sturm series was termed “CNS neuroblastoma with FOXR2 activation”. As the name implies, the tumors with FOXR2 activation often showed histologic and immunohistochemical evidence of neuronal and potentially, even ganglion cell differentiation, but in contrast to most other neuroblastic tumors, they coexpressed OLIG2 (Fig. 8). Molecularly,
9
Journal Pre-proof there were various structural alterations resulting in upregulation of FOXR2, including recurrent FOXR2 tandem duplications and JMJDIC-FOXR2 fusions, often in association with gain of chromosome arm 1q [27].
CNS Ewing sarcoma family tumor with CIC alteration Another group of 12 tumors from the Sturm series was termed “CNS Ewing sarcoma family
of
tumor with CIC alteration”. The CIC-altered tumors showed genetic and histologic overlap with
ro
CIC-rearranged round cell sarcomas outside the CNS, including recurrent CIC-NUTM1 fusions
-p
[27]. They also overlap morphologically with the HGNET BCOR exon 15 ITD entity described
re
above. As such, it remains unclear whether the tumors in the CNS represent a novel entity or the
na
Astroblastoma with MN1 fusion
lP
same CIC-rearranged round cell sarcomas as encountered elsewhere.
Astroblastoma is a rare glial neoplasm with features overlapping those of conventional
ur
astrocytoma and ependymoma. Histologically, the tumor shows a mostly solid growth pattern
Jo
with extensive stromal and/or perivascular sclerosis and is composed of oval to epithelioid neoplastic cells that form broad (rather than fibrillar) cell processes with radial arrangements around central blood vessels (astroblastic pseudorosettes); the most cellular forms may also resemble a small round cell neoplasm (Fig. 9). They typically occur in children to young adults and have variable biological behavior. They lack IDH1/2 mutations characteristic of diffuse gliomas in adults. No recurrent genetic alterations had been described for this entity prior to 2016. A study by Lehman demonstrated BRAFV600E mutation through targeted sequencing in
10
Journal Pre-proof eight of 21 cases [34]. However, since pleomorphic xanthoastrocytomas (PXA) occasionally show an “astroblastic pattern”, it is possible that these were in fact, PXA. A group of 11 tumors from the Sturm series were termed “CNS HGNET with MN1 alteration”. These tumors with MN1 fusions most often, though not invariably, showed histologic features resembling “astroblastoma”. They harbored frequent in-frame fusions between MN1 and BEND2 via a t(22;X)(q12;p22) translocation [27]. The proposed diagnostic term of “CNS
of
HGNET with MN1 alteration” may not be appropriate since virtually all reported patients to date
ro
have survival times of many years or even decades, and many astroblastomas with MN1 fusions
-p
in follow up studies have had minimal proliferative activity and lacked high-grade histologic
re
features. Additionally, these tumors consistently demonstrate evidence of purely glial/ependymal differentiation.
lP
A subsequent series of histologically diagnosed astroblastomas by Hirose et al reported
na
rearrangements of MN1 by fluorescence in situ hybridization (FISH) in five of eight tumors [35]. Another series of eight histologically-defined astroblastomas was examined with targeted next
ur
generation sequencing by Wood et al. Of the eight tumors, two pediatric tumors showed solitary
Jo
MN1 alterations, two adult tumors showed MN1 alterations with additional pathogenic genetic alterations (CDKN2A/B homozygous deletion, TP53, ATM, and TERT promoter mutations), one showed genetic features of anaplastic pleomorphic xanthoastrocytoma (BRAFV600E mutation, CDKN2A/B homozygous deletion, and TERT promotor mutation), and another showed genetic features of IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification, and TP53, NRAS, and TERT promoter mutations) [36]. Three of the four MN1-altered tumors clustered together with those tumors described by Sturm et al as “high-grade neuroepithelial tumor with MN1 alteration” by genome-wide methylation profiling. Two of the eight cases did
11
Journal Pre-proof not show defining genetic alterations despite multimodal molecular analysis. Another recently published series of histologically-defined astroblastomas was similarly found to be genetically heterogeneous. Of the 27 tumors, ten demonstrated MN1 rearrangements, seven demonstrated BRAFV600E mutations, two demonstrated RELA rearrangements, and the remaining eight cases lacked any specific genetic alterations. By methylation profiling, the tumors with BRAFV600E mutations clustered with pleomorphic xanthoastrocytoma and the tumors with RELA
of
rearrangement clustered with RELA-fusion ependymoma. The ten tumors with MN1
ro
rearrangement clustered together with those tumors described by Sturm et al as “high-grade
-p
neuroepithelial tumor with MN1 alteration.” Survival analysis revealed excellent overall survival
re
in the MN1-altered astroblastomas [37].
These recent studies of astroblastoma with multimodal molecular analysis demonstrate that
lP
histologically-defined astroblastoma is likely a heterogenous group of tumors with variable
na
clinical courses that is better delineated with additional genetic testing. As such, astroblastoma likely represents both a specific entity and a histologic pattern that is occasionally encountered in
ur
other CNS neoplasms. We and others have therefore proposed that those astroblastomas with
Jo
MN1 fusions represent the “true” astroblastomas and have recommended the terminology “astroblastoma, MN1 fusion-positive” as the nomenclature for this entity moving forward.
CONCLUSIONS
The increasing literature characterizing the genetics of central nervous system neoplasms continues to contribute to our understanding of tumor biology and enhances our ability to
12
Journal Pre-proof subclassify brain tumors accurately and objectively. A number of entity-defining alterations have been identified in primary central nervous system tumors since the WHO 2016 scheme was published. Separation of entities with overlapping histologic features into more specific molecularly defined diagnoses is also possible. Therefore, the practice of diagnostic neuropathology is rapidly evolving to include integrated histopathologic and molecular data with
Jo
ur
na
lP
re
-p
ro
of
the benefit of increased diagnostic and prognostic fidelity.
13
Journal Pre-proof Fig. 1 Multinodular and vacuolating neuronal tumor. A, Low-power microscopy showing discrete nodules within the subcortical white matter. B, High-power microscopy of the nodules reveals small- to medium-sized neuronal cells with prominent intracytoplasmic and stromal vacuoles. Immunostains for synaptophysin (C) and OLIG2 (D) are positive in tumor cells. Fig. 2 Chordoid glioma. A, T2-weighted head MRI demonstrating a mass centered in the anterior third ventricle. B, Histology reveals chordoma-like clusters and cords of epithelioid tumors cells embedded within a mucinous stroma. A lymphoplasmacyte-rich inflammatory infiltrate can be seen at the periphery. C, An Alcian blue stain highlights the mucinous stroma. D, The GFAP immunostain shows strong cytoplasmic staining in tumor cells.
-p
ro
of
Fig. 3 Pineal parenchymal tumors. A, A pineoblastoma composed of sheets of small immature neuroepithelial cells with hyperchromatic nuclei, nuclear molding, and cell wrapping. Frequent mitoses and occasional Homer Wright rosettes are present. B, A pineal parenchymal tumor of intermediate differentiation composed of sheets of uniform round cells with mild to moderate atypia and occasional mitotic figures, but lacking the primitive appearance of pineoblastoma.
lP
re
Fig. 4 Extraventricular neurocytoma. A, Solid appearing neoplasm composed of small, uniform, round neurocyte-like cells embedded within a fibrillar neuropil-rich background. B, The synaptophysin immunostain highlights the neuropil within neurocytic rosettes.
na
Fig. 5 Polymorphous low grade neuroepithelial tumor of the young. A, A calcific oligodendroglioma-like neoplasm with delicate arborizing vasculature. B, The CD34 immunostain is strongly and diffusely positive in tumor cells.
ur
Fig. 6 Myxoid glioneuronal tumor. A, Post-contrast MRI demonstrating a mass centered in the septum pellucidum. B, Histology revealed a columnar architecture with oligodendroglial-like cells embedded in a mucin-rich stroma and “floating” neurons.
Jo
Fig. 7 High-grade neuroepithelial tumor with BCOR internal tandem duplication. A, A neoplasm with solid growth pattern and areas of palisading necrosis. B, Tumor cells with oval to tapered nuclei, variably fibrillar processes, and perivascular pseudorosettes. C, The BCOR immunostain shows strong nuclear immunoreactivity. Fig. 8 CNS neuroblastoma with FOXR2 activation. A, Sheet-like architecture with small round cells forming vascular pseudorosettes. A subset of the tumor cells demonstrated neurocytic and ganglion cell cytologic features. B, The immunostain for OLIG2 is positive. Fig. 9 Astroblastoma with MN1 fusion. A, The tumor shows a solid growth pattern with oval to epithelioid cells forming broad processes and radial arrangements around central blood vessels in a background of extensive stromal sclerosis. B, The GFAP stain showed strong cytoplasmic staining but a lack of the fibrillar processes typically seen in ependymoma.
14
Journal Pre-proof REFERENCES 1. Louis DN, Ohgaki H, Wiestler OD, et al, editors. WHO classification of tumours of the central nervous system. 4th Revised ed. Lyon: WHO;2016. 2. Cathcart SJ, Klug JR, Helvey JT, L white M, Gard AP, Mccomb RD. Multinodular and Vacuolating Neuronal Tumor: A Rare Seizure-associated Entity. Am J Surg Pathol 2017;41:1005-10. 3. Thom M, Liu J, Bongaarts A, et al. Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?. Brain Pathol 2018;28:155-71.
ro
of
4. Pekmezci M, Stevers M, Phillips JJ, et al. Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta Neuropathol 2018;135:485-8.
-p
5. Goode B, Mondal G, Hyun M, et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 2018;9:810.
re
6. Rosenberg S, Simeonova I, Bielle F, et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat Commun 2018;9:2371.
lP
7. De jong MC, Kors WA, De graaf P, Castelijns JA, Kivelä T, Moll AC. Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 2014;15(10):1157-67.
ur
na
8. Gadish T, Tulchinsky H, Deutsch AA, Rabau M. Pinealoblastoma in a patient with familial adenomatous polyposis: variant of Turcot syndrome type 2? Report of a case and review of the literature. Dis Colon Rectum 2005;48:2343-6.
Jo
9. De kock L, Sabbaghian N, Druker H, et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 2014;128:583-95. 10. Snuderl M, Kannan K, Pfaff E, et al. Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun 2018;9:2868. 11. Rakheja D, Chen KS, Liu Y, et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2014;2:4802. 12. Lee JC, Mazor T, Lao R, et al. Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma. Acta Neuropathol 2019;137:851-4. 13. Perry A, Scheithauer BW, Macaulay RJ, Raffel C, Roth KA, Kros JM. Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with diagnostic and histogenetic implications. J Neuropathol Exp Neurol 2002;61:947-55. 15
Journal Pre-proof
14. Sievers P, Stichel D, Schrimpf D, et al. FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathol 2018;136:293-302. 15. Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012;337:1231-5. 16. Lasorella A, Sanson M, Iavarone A. FGFR-TACC gene fusions in human glioma. Neurooncology 2017;19:475-483.
of
17. Rivera B, Gayden T, Carrot-zhang J, et al. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 2016;131:847-63.
ro
18. Qaddoumi I, Orisme W, Wen J, et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 2016;131:833-45.
re
-p
19. Sievers P, Appay R, Schrimpf D, et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol 2019 June 27 [Epub ahead of print].
na
lP
20. Huse JT, Snuderl M, Jones DT, et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 2017;133:417-429.
ur
21. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397-405.
Jo
22. Solomon DA, Korshunov A, Sill M, et al. Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNTlike methylation profile. Acta Neuropathol 2018;136:339-43. 23. Lucas CG, Villanueva-meyer JE, Whipple N, et al. Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. Brain Pathol 2019 October 14 [Epub ahead of print]. 24. Chiang JCH, Harreld JH, Tanaka R, et al. Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis. Neuro-oncology 2019;21:800-8. 25. Paugh BS, Zhu X, Qu C, et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 2013;73:6219-29.
16
Journal Pre-proof 26. Trabelsi S, Chabchoub I, Ksira I, et al. Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population. Mol Neurobiol 2017;54:2381-94. 27. Sturm D, Orr BA, Toprak UH, et al. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 2016;164:1060-72. 28. Meredith DM. Advances in Diagnostic Immunohistochemistry for Primary Tumors of the Central Nervous System. Adv Anat Pathol 2019 February 1 [Epub ahead of print].
of
29. Appay R, Macagno N, Padovani L, et al. HGNET-BCOR Tumors of the Cerebellum: Clinicopathologic and Molecular Characterization of 3 Cases. Am J Surg Pathol 2017;41:125460.
ro
30. Ferris SP, Velazquez vega J, Aboian M, et al. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol 2019 May 18 [Epub ahead of print].
re
-p
31. Yoshida Y, Nobusawa S, Nakata S, et al. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol 2018;28:710-20.
lP
32. Ueno-yokohata H, Okita H, Nakasato K, et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 2015;47:861-3.
ur
na
33. Kao YC, Sung YS, Zhang L, et al. Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 2016;40:1009-20.
Jo
34. Lehman NL, Hattab EM, Mobley BC, et al. Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults. Neuro-oncology 2017;19:31-42. 35. Hirose T, Nobusawa S, Sugiyama K, et al. Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement. Brain Pathol 2018;28:684-94. 36. Wood MD, Tihan T, Perry A, et al. Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol 2018;28:192202. 37. Lehman NL, Usubalieva A, Lin T, et al. Genomic analysis demonstrates that histologicallydefined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis. Acta Neuropathol Commun 2019;7:42.
17
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Calixto-Hope G. Lucas, David A. Solomon, Arie Perry PII:
S0046-8177(19)30191-1
DOI:
https://doi.org/10.1016/j.humpath.2019.10.009
Reference:
YHUPA 4939
To appear in:
Human Pathology
Received date:
21 October 2019
Accepted date:
24 October 2019
Please cite this article as: C.-H.G. Lucas, D.A. Solomon and A. Perry, A review of recently described genetic alterations in central nervous system tumors, Human Pathology(2019), https://doi.org/10.1016/j.humpath.2019.10.009
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof A Review of Recently Described Genetic Alterations in Central Nervous System Tumors Calixto-Hope G. Lucas1, David A. Solomon1,2 Arie Perry1,3
ro
Corresponding author: Arie Perry, MD Department of Pathology, Division of Neuropathology University of California, San Francisco 505 Parnassus Avenue, Room M551 San Francisco, California 94143 Phone: (415) 476 - 5236 Email: [email protected]
of
1. Department of Pathology, University of California, San Francisco, CA, USA 2. Clinical Cancer Genomics Laboratory, University of California, San Francisco, CA, USA 3. Department of Neurological Surgery, University of California, San Francisco, CA, USA
re
-p
Key words: CNS tumors, molecular neuropathology, targeted next-generation sequencing, multinodular vacuolating neuronal tumor, chordoid glioma, pineal parenchymal tumor, extraventricular neurocytoma, polymorphous low grade neuroepithelial tumor of the young, myxoid glioneuronal tumor, CNS embryonal tumors, BCOR, FOXR2, CIC, MN1
Jo
ur
na
lP
This manuscript has not been previously published or submitted elsewhere for review. The authors declare no conflicts of interest. D.A.S is supported by NIH Director’s Early Independence Award (DP5 OD021403).
Journal Pre-proof INTRODUCTION
Advances in molecular profiling of central nervous system tumors have enabled the development of classification schemes with improved diagnostic and prognostic accuracy. As such, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) introduced a paradigm shift in the diagnosis of brain tumors [1]. For instance, integrated
of
assessment incorporating both histologic features and genetic alterations was introduced into the
ro
diagnostic framework of gliomas. IDH1/2 mutation status now represents the most important
-p
initial stratifier of diffuse gliomas in adults, although rarer subtypes within the IDH-wildtype
re
category continue to be elucidated. Medulloblastomas and other embryonal neoplasms were also genetically defined and segregated based on molecular subtypes, and one molecular subtype of
lP
ependymoma was added. In this review, we summarize the rapidly evolving spectrum of
na
recurrent genetic alterations described in central nervous system tumor entities since the
ur
publication of the WHO 2016.
Jo
PREVIOUSLY RECOGNIZED ENTITIES WITH NEWLY DESCRIBED GENETIC ALTERATIONS
Multinodular and vacuolating neuronal tumor Multinodular and vacuolating neuronal tumor of the cerebrum (MVNT) is a low-grade neuronal neoplasm of the cerebral hemispheres recently added to the WHO 2016 as a potential subtype of gangliocytoma/ganglioglioma or other glioneuronal neoplasm. Histologically, the tumor is composed of nodules of small- to medium-sized neuronal cells with prominent intracytoplasmic
1
Journal Pre-proof and stromal vacuoles (Fig. 1). Tumors are commonly located in the deep cortex and subcortical white matter of the temporal lobe. As such, patients typically present with seizures. Given the limited literature at publication, the WHO 2016 did not delineate whether MVNT is a neoplastic or hamartomatous process. Some targeted next-generation sequencing studies failed to find any recurrent mutations in genes commonly altered in other low-grade brain tumors (mTOR pathway genes, BRAF, FGFR1, or MYB), potentially indicating that MVNT could be malformative [2,3].
of
However, in a series by Pekmezci et al, recurrent and mutually exclusive mutations in MAP2K1
ro
and BRAF were identified [4]. Out of eight sequenced tumors, five demonstrated missense
-p
mutations or small in-frame deletions within exon 2 of the MAP2K1 gene, two cases
re
demonstrated mutations other than the more common p.V600E variant in the BRAF gene, and one case demonstrated an FGFR2-INA in-frame gene fusion. These findings confirm that MVNT
lP
is a clonal neoplasm characterized by solitary pathogenic alterations that cause activation of the
ur
Chordoid glioma
na
Ras-Raf-MAP kinase signaling pathway.
Jo
Chordoid glioma of the third ventricle (WHO grade II) is a rare, slow-growing, non-invasive glial tumor. Histologically, the tumor exhibits chordoma-like clusters and cords of epithelioid tumors cells embedded within a mucinous stroma and often surrounded by a lymphoplasmacyterich inflammatory infiltrate (Fig. 2). They typically occur in adults and present with obstructive symptoms or endocrine abnormalities. Due to their location in the anterior third ventricle, gross total resection is often challenging, with tumor progression and even patient death being relatively common despite slow growth rates. No recurrent genetic abnormalities were described prior to 2016, but two recently published series have demonstrated a signature PRKCA mutation.
2
Journal Pre-proof In a series of 13 chordoid gliomas, Goode et al identified a recurrent p.D463H missense mutation in PRKCA in all 13 tumors [5]. In a concurrently published series of 16 chordoid gliomas, Rosenberg et al demonstrated the identical p.D463H missense mutation in PRKCA in 15 tumors [6]. The missense mutation localizes within the active site of the kinase domain of the encoded protein kinase C alpha and has not been reported in any other tumor type to date. Together, these studies identify PRKCA p.D463H as a recurrent and specific oncogenic mutation in chordoid
ro
of
gliomas, also providing a potential therapeutic target for further treatment after surgery.
-p
Pineal parenchymal tumors
re
Pineal parenchymal tumors consist of a spectrum of neoplasms that arise from the specialized neuronal cells of the pineal gland and include pineocytoma (WHO grade I), pineal parenchymal
lP
tumor of intermediate differentiation (WHO grade II or III), and pineoblastoma (WHO grade
na
IV). All of them stain diffusely with synaptophysin, while neurofilament expression is roughly inversely proportional to grade.
ur
Pineoblastoma is a rare, malignant embryonal neoplasm of the pineal gland that usually occurs in
Jo
children and young adults. The tumor is composed of sheets of small immature neuroepithelial cells with frequent mitoses. Occasional areas with Homer Wright and Flexner-Wintersteiner rosettes may be seen (Fig. 3A). Genetically, associations with hereditary retinoblastoma (socalled “trilateral retinoblastoma”) and familial adenomatous polyposis have been reported [7,8]. A portion of pineoblastomas develop in patients with germline and/or somatic DICER1 mutations [9]. A recent publication has also demonstrated recurrent homozygous deletions of DROSHA in pineoblastoma. In a series of 19 sequenced sporadic pineoblastomas, homozygous deletion of DROSHA was identified in five cases [10]. DROSHA is involved in miRNA
3
Journal Pre-proof processing in the nucleus, upstream of DICER1 [11]. Another recent series of four pineoblastomas by Lee et al showed somatic DICER1 mutations in two tumors and homozygous deletion of DROSHA in the other two tumors [12]. Together, these data implicate dysregulation of miRNA processing as a central theme in the pathogenesis of pineoblastoma. Pineal parenchymal tumors of intermediate differentiation (PPTID) are tumors of the pineal gland with biologic behavior that is better than pineoblastoma but worse than pineocytoma. They
of
can be composed of sheets or lobules of uniform round cells with mild to moderate atypia and
ro
mitotic figures, but they otherwise lack the primitive (hyperchromatic nuclei, nuclear molding,
-p
cell wrapping, etc.) appearance of pineoblastoma (Fig. 3B). In contrast to pineoblastomas,
re
PPTIDs have not been found to have DICER1 or DROSHA alterations. Instead, the series of by Lee et al demonstrated an in-frame insertion (p.R313delinsPRR) in the KBTBD4 gene in all three
lP
PPTIDs examined [12]. As such, these mutations may be diagnostically useful in distinguishing
na
pineoblastoma and pineal parenchymal tumors of intermediate differentiation from one another, although larger studies are still needed to more fully elucidate the genetic spectrum.
ur
To date, no signature genetic alterations have been reported in the literature for pineocytoma,
Jo
which features a more mature appearance including a ‘salt and pepper’ chromatin pattern, low mitotic index, and prominent pineocytic rosettes.
Extraventricular neurocytoma Extraventricular neurocytoma (WHO grade II) is a rare neuronal neoplasm that can present throughout the central nervous system parenchyma, but otherwise resembles the central neurocytoma encountered within the lateral ventricles. Tumors are histologically heterogeneous but display a mostly solid growth pattern and are composed of small, uniform round
4
Journal Pre-proof oligodendrocyte-like or neurocyte-like cells (i.e. small mature neurons), often with perinuclear clear haloes; neuronal differentiation is evident in the form of neuropil formation, neurocytic rosettes (with central neuropil similar in appearance to pineocytic rosettes), and diffuse synaptophysin immunoreactivity (Fig. 4). Other common features include limited ganglion cell differentiation, hyalinized vessels, and calcifications. Co-deletion of chromosome arms 1p and 19q and mutations of IDH1 or IDH2 mutation are absent by definition, thereby excluding the
of
alternate diagnostic consideration of oligodendroglioma with extensive neurocytic differentiation
ro
[13]. No genomic studies had been performed prior to the WHO 2016 scheme. However, a recent
-p
series of 15 sequenced extraventricular neurocytomas by Sievers et al demonstrated frequent
re
FGFR family alterations. They found FGFR gene rearrangements in 11 tumors, eight showing FGFR1-TACC1 fusion, one with FGFR1-EVI5 fusion, and the remaining two with FGFR3-
lP
TACC3 fusion [14]. FGFR fusions are thought to drive enhanced downstream signaling through
na
MAP kinase pathway effectors by way of homodimerization and autophosphorylation mediated by coiled coil domains resident in their respective fusion partners [15,16]. Although first
ur
described in glioblastoma, FGFR-TACC gene fusions have also been described in low-grade
Jo
brain tumors, including dysembryoplastic neuroepithelial tumor (DNT) [17], pediatric-type IDHwildtype oligodendroglioma [18], and rosette-forming glioneuronal tumor (RGNT) [19], albeit not at the higher frequency reported in the extraventricular neurocytoma series. Tumorigenic drivers, including FGFR gene alterations, have not been reported in central neurocytoma to date.
NEWLY PROPOSED ENTITIES WITH SIGNATURE MOLECULAR ALTERATIONS
Polymorphous low grade neuroepithelial tumor of the young
5
Journal Pre-proof Polymorphous low grade neuroepithelial tumor of the young (PLNTY) is a recently proposed morphologically and molecularly distinct tumor entity within the spectrum of low-grade epilepsy-associated glioneuronal tumors. Microscopic findings include an infiltrative, often heavily calcified oligodendroglioma-like neoplasm, but with variable neuronal features and a hallmark immunohistochemical finding of intense immunolabeling for CD34 (Fig. 5). Molecular profiling of a series of PLNTYs has shown frequent genetic alterations in BRAF and FGFR
of
family genes. In a series of eight PLNTY tumors published by Huse et al, three tumors harbored
ro
BRAFV600E mutations while another four had various FGFR family alterations. Of the four
-p
tumors with FGFR alterations, one showed an FGFR3-TACC3 fusion, one showed an FGFR2-
re
CTNNA3 fusion, and two showed FGFR2-KIAA1598 fusions [20]. As mentioned previously, FGFR fusions are thought to upregulate signaling and activation of the downstream MAP kinase
lP
pathways; these alterations are not specific to PLNTY. Similarly, MAP kinase activation through
na
BRAFV600E mutation has been implicated in numerous other low-grade epileptogenic tumors including gangliogliomas and pleomorphic xanthoastrocytomas [21]. The cases reported to date
ur
have followed benign clinical courses. While not characterized by any one signature genetical
Jo
alteration, the unique combined morphologic, immunohistochemical, and molecular profile of these tumors suggest that PLNTY represents a distinct biological entity.
Myxoid glioneuronal tumor Myxoid glioneuronal tumor is a newly proposed tumor entity that arises in the septum pellucidum, corpus callosum, or periventricular white matter and harbors a unique genetic alteration. These tumors usually show a columnar arrangement of oligodendroglial-like cells in a mucin-rich stroma with “floating” ganglion cells, reminiscent of DNT (Fig. 6). However, they
6
Journal Pre-proof lack the multinodular architecture with mucin-rich patterned nodules typical of cortically-based DNT. A subset also features neurocytic rosettes, similar to rosette-forming glioneuronal tumor (RGNT). These DNT- and RGNT-like neoplasms arising in the septum pellucidum have been described previously, but comprehensive molecular characterization has only recently been performed with multiple series showing that these myxoid glioneuronal tumors possess a specific and recurrent mutation in PDGFRA. In a series by Solomon et al, all four sequenced cases of
of
myxoid glioneuronal tumor showed dinucleotide substitutions in the PDGFRA gene, three with
ro
p.K385L and one with p.K385I. The dinucleotide substitution resides within the region encoding
-p
extracellular immunoglobulin-like C2-type domain 4 [22]. Some of the above described myxoid
re
glioneuronal tumors demonstrated intraventricular dissemination but otherwise exhibited benign behavior [23]. In a series of similar tumors involving the septum pellucidum by Chiang et al, 13
lP
of 18 cases showed the identical PDGFRA dinucleotide mutations [24]. Of 14 tumors with
na
PDGFRA mutations, 11 had p.K385L and 2 had p.K385I, whereas one other had p.E365insKW insertion. Three of the four tumors without PDGFRA mutations had FGFR1 alterations and the
ur
remaining tumor had an NF1 mutation, suggesting that they may have been pilocytic
Jo
astrocytomas instead. PDGFRA mutations have been reported in high-grade diffuse gliomas but occur invariably in conjunction with other pathogenic alterations such as TERT promoter mutation, CDKN2A homozygous deletion, or mutation in H3F3A or HIST1H3B [25,26]. To date, PDGFRA mutations have not been identified as the solitary genetic driver in any central nervous system tumors, including cortically-based DNT. The findings therefore argue that myxoid glioneuronal tumor is a distinct tumor entity.
Central nervous system embryonal tumors
7
Journal Pre-proof Previously classified as “primitive neuroectodermal tumors” (PNETs), central nervous system (CNS) embryonal tumors represent a biologically heterogenous group of highly malignant “small round cell” tumors with variable evidence of neuronal, astrocytic, myogenic, and/or melanocytic differentiation. Various genetic alterations have been described that are used to define the different subtypes. These include C19MC amplification in embryonal tumor with multilayered rosettes (added as an entity in the WHO 2016) and either SMARCB1 or SMARCA4 biallelic
of
inactivation in atypical teratoid/rhabdoid tumor [1]. However, other central nervous system
ro
embryonal tumors lacking distinctive histologic or genetic features remain diagnostically
-p
challenging.
re
Comprehensive genetic analysis by Sturm et al of a large cohort of tumors previously classified as CNS PNETs revealed that most could be reclassified as other well-established entities when
lP
studied genomically; however, several new and distinct molecular subgroups emerged. Of 323
na
tumors studied by DNA methylation profiling, 36 were reclassified as embryonal tumor with multilayered rosettes, 15 as supratentorial ependymomas, 14 as atypical teratoid/rhabdoid
ur
tumors, and 10 as H3 K27M-mutant diffuse midline gliomas, among others. In contrast, 77
Jo
formed four distinct methylation groups with unique genetic alterations that did not overlap with any previously known central nervous system tumor entities and as such, new entities were proposed [27].
High-grade neuroepithelial tumor with BCOR internal tandem duplication One group of ten tumors from the Sturm series is termed “high-grade neuroepithelial tumor (HGNET) with BCOR internal tandem duplication”. These tumors presented within the first year of life and occurred throughout the neuraxis. Histologically, in addition to primitive features, the
8
Journal Pre-proof tumors showed some overlapping features with glioblastoma and ependymoma, including solid growth, oval to tapered nuclei, variably fibrillar processes, perivascular pseudorosettes (albeit often GFAP negative), and areas of palisading necrosis (Fig. 7A-B). This entity shows robust upregulation of BCOR and activation of the WNT pathway that can be detected by nuclear immunostaining for BCOR (Fig. 7C) and beta-catenin respectively [28]. This entity often leads to death within a few months of diagnosis, although occasional long-term survivors have been
of
described [29,30]. This tumor entity is genetically defined by an internal tandem duplication
ro
within exon 15 of the BCOR transcriptional corepressor gene [29,31]. The same alteration has
-p
been described in other tumor types outside of the central nervous system, including clear cell
re
sarcoma of the kidney and primitive myxoid mesenchymal tumor of [32,33]. In a series by Ferris et al, the BCOR exon 15 internal tandem duplication (ex15 ITD) was the solitary pathogenic
lP
alteration identified in six of ten cases; The remaining four cases showed various additional
na
pathogenic alterations including CDKN2A/B homozygous deletion, TERT amplification or promotor hotspot mutation, or damaging mutations in TP53, BCORL1, EP300, SMARCA2, and
ur
STAG2 [30]. They also suggested the more specific nomenclature of HGNET with BCOR exon
Jo
15 ITD for this tumor entity, since a wide range of other CNS tumor types harbor BCOR alterations other than the exon 15 ITD.
CNS neuroblastoma with FOXR2 activation A separate group of 44 tumors in the Sturm series was termed “CNS neuroblastoma with FOXR2 activation”. As the name implies, the tumors with FOXR2 activation often showed histologic and immunohistochemical evidence of neuronal and potentially, even ganglion cell differentiation, but in contrast to most other neuroblastic tumors, they coexpressed OLIG2 (Fig. 8). Molecularly,
9
Journal Pre-proof there were various structural alterations resulting in upregulation of FOXR2, including recurrent FOXR2 tandem duplications and JMJDIC-FOXR2 fusions, often in association with gain of chromosome arm 1q [27].
CNS Ewing sarcoma family tumor with CIC alteration Another group of 12 tumors from the Sturm series was termed “CNS Ewing sarcoma family
of
tumor with CIC alteration”. The CIC-altered tumors showed genetic and histologic overlap with
ro
CIC-rearranged round cell sarcomas outside the CNS, including recurrent CIC-NUTM1 fusions
-p
[27]. They also overlap morphologically with the HGNET BCOR exon 15 ITD entity described
re
above. As such, it remains unclear whether the tumors in the CNS represent a novel entity or the
na
Astroblastoma with MN1 fusion
lP
same CIC-rearranged round cell sarcomas as encountered elsewhere.
Astroblastoma is a rare glial neoplasm with features overlapping those of conventional
ur
astrocytoma and ependymoma. Histologically, the tumor shows a mostly solid growth pattern
Jo
with extensive stromal and/or perivascular sclerosis and is composed of oval to epithelioid neoplastic cells that form broad (rather than fibrillar) cell processes with radial arrangements around central blood vessels (astroblastic pseudorosettes); the most cellular forms may also resemble a small round cell neoplasm (Fig. 9). They typically occur in children to young adults and have variable biological behavior. They lack IDH1/2 mutations characteristic of diffuse gliomas in adults. No recurrent genetic alterations had been described for this entity prior to 2016. A study by Lehman demonstrated BRAFV600E mutation through targeted sequencing in
10
Journal Pre-proof eight of 21 cases [34]. However, since pleomorphic xanthoastrocytomas (PXA) occasionally show an “astroblastic pattern”, it is possible that these were in fact, PXA. A group of 11 tumors from the Sturm series were termed “CNS HGNET with MN1 alteration”. These tumors with MN1 fusions most often, though not invariably, showed histologic features resembling “astroblastoma”. They harbored frequent in-frame fusions between MN1 and BEND2 via a t(22;X)(q12;p22) translocation [27]. The proposed diagnostic term of “CNS
of
HGNET with MN1 alteration” may not be appropriate since virtually all reported patients to date
ro
have survival times of many years or even decades, and many astroblastomas with MN1 fusions
-p
in follow up studies have had minimal proliferative activity and lacked high-grade histologic
re
features. Additionally, these tumors consistently demonstrate evidence of purely glial/ependymal differentiation.
lP
A subsequent series of histologically diagnosed astroblastomas by Hirose et al reported
na
rearrangements of MN1 by fluorescence in situ hybridization (FISH) in five of eight tumors [35]. Another series of eight histologically-defined astroblastomas was examined with targeted next
ur
generation sequencing by Wood et al. Of the eight tumors, two pediatric tumors showed solitary
Jo
MN1 alterations, two adult tumors showed MN1 alterations with additional pathogenic genetic alterations (CDKN2A/B homozygous deletion, TP53, ATM, and TERT promoter mutations), one showed genetic features of anaplastic pleomorphic xanthoastrocytoma (BRAFV600E mutation, CDKN2A/B homozygous deletion, and TERT promotor mutation), and another showed genetic features of IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification, and TP53, NRAS, and TERT promoter mutations) [36]. Three of the four MN1-altered tumors clustered together with those tumors described by Sturm et al as “high-grade neuroepithelial tumor with MN1 alteration” by genome-wide methylation profiling. Two of the eight cases did
11
Journal Pre-proof not show defining genetic alterations despite multimodal molecular analysis. Another recently published series of histologically-defined astroblastomas was similarly found to be genetically heterogeneous. Of the 27 tumors, ten demonstrated MN1 rearrangements, seven demonstrated BRAFV600E mutations, two demonstrated RELA rearrangements, and the remaining eight cases lacked any specific genetic alterations. By methylation profiling, the tumors with BRAFV600E mutations clustered with pleomorphic xanthoastrocytoma and the tumors with RELA
of
rearrangement clustered with RELA-fusion ependymoma. The ten tumors with MN1
ro
rearrangement clustered together with those tumors described by Sturm et al as “high-grade
-p
neuroepithelial tumor with MN1 alteration.” Survival analysis revealed excellent overall survival
re
in the MN1-altered astroblastomas [37].
These recent studies of astroblastoma with multimodal molecular analysis demonstrate that
lP
histologically-defined astroblastoma is likely a heterogenous group of tumors with variable
na
clinical courses that is better delineated with additional genetic testing. As such, astroblastoma likely represents both a specific entity and a histologic pattern that is occasionally encountered in
ur
other CNS neoplasms. We and others have therefore proposed that those astroblastomas with
Jo
MN1 fusions represent the “true” astroblastomas and have recommended the terminology “astroblastoma, MN1 fusion-positive” as the nomenclature for this entity moving forward.
CONCLUSIONS
The increasing literature characterizing the genetics of central nervous system neoplasms continues to contribute to our understanding of tumor biology and enhances our ability to
12
Journal Pre-proof subclassify brain tumors accurately and objectively. A number of entity-defining alterations have been identified in primary central nervous system tumors since the WHO 2016 scheme was published. Separation of entities with overlapping histologic features into more specific molecularly defined diagnoses is also possible. Therefore, the practice of diagnostic neuropathology is rapidly evolving to include integrated histopathologic and molecular data with
Jo
ur
na
lP
re
-p
ro
of
the benefit of increased diagnostic and prognostic fidelity.
13
Journal Pre-proof Fig. 1 Multinodular and vacuolating neuronal tumor. A, Low-power microscopy showing discrete nodules within the subcortical white matter. B, High-power microscopy of the nodules reveals small- to medium-sized neuronal cells with prominent intracytoplasmic and stromal vacuoles. Immunostains for synaptophysin (C) and OLIG2 (D) are positive in tumor cells. Fig. 2 Chordoid glioma. A, T2-weighted head MRI demonstrating a mass centered in the anterior third ventricle. B, Histology reveals chordoma-like clusters and cords of epithelioid tumors cells embedded within a mucinous stroma. A lymphoplasmacyte-rich inflammatory infiltrate can be seen at the periphery. C, An Alcian blue stain highlights the mucinous stroma. D, The GFAP immunostain shows strong cytoplasmic staining in tumor cells.
-p
ro
of
Fig. 3 Pineal parenchymal tumors. A, A pineoblastoma composed of sheets of small immature neuroepithelial cells with hyperchromatic nuclei, nuclear molding, and cell wrapping. Frequent mitoses and occasional Homer Wright rosettes are present. B, A pineal parenchymal tumor of intermediate differentiation composed of sheets of uniform round cells with mild to moderate atypia and occasional mitotic figures, but lacking the primitive appearance of pineoblastoma.
lP
re
Fig. 4 Extraventricular neurocytoma. A, Solid appearing neoplasm composed of small, uniform, round neurocyte-like cells embedded within a fibrillar neuropil-rich background. B, The synaptophysin immunostain highlights the neuropil within neurocytic rosettes.
na
Fig. 5 Polymorphous low grade neuroepithelial tumor of the young. A, A calcific oligodendroglioma-like neoplasm with delicate arborizing vasculature. B, The CD34 immunostain is strongly and diffusely positive in tumor cells.
ur
Fig. 6 Myxoid glioneuronal tumor. A, Post-contrast MRI demonstrating a mass centered in the septum pellucidum. B, Histology revealed a columnar architecture with oligodendroglial-like cells embedded in a mucin-rich stroma and “floating” neurons.
Jo
Fig. 7 High-grade neuroepithelial tumor with BCOR internal tandem duplication. A, A neoplasm with solid growth pattern and areas of palisading necrosis. B, Tumor cells with oval to tapered nuclei, variably fibrillar processes, and perivascular pseudorosettes. C, The BCOR immunostain shows strong nuclear immunoreactivity. Fig. 8 CNS neuroblastoma with FOXR2 activation. A, Sheet-like architecture with small round cells forming vascular pseudorosettes. A subset of the tumor cells demonstrated neurocytic and ganglion cell cytologic features. B, The immunostain for OLIG2 is positive. Fig. 9 Astroblastoma with MN1 fusion. A, The tumor shows a solid growth pattern with oval to epithelioid cells forming broad processes and radial arrangements around central blood vessels in a background of extensive stromal sclerosis. B, The GFAP stain showed strong cytoplasmic staining but a lack of the fibrillar processes typically seen in ependymoma.
14
Journal Pre-proof REFERENCES 1. Louis DN, Ohgaki H, Wiestler OD, et al, editors. WHO classification of tumours of the central nervous system. 4th Revised ed. Lyon: WHO;2016. 2. Cathcart SJ, Klug JR, Helvey JT, L white M, Gard AP, Mccomb RD. Multinodular and Vacuolating Neuronal Tumor: A Rare Seizure-associated Entity. Am J Surg Pathol 2017;41:1005-10. 3. Thom M, Liu J, Bongaarts A, et al. Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?. Brain Pathol 2018;28:155-71.
ro
of
4. Pekmezci M, Stevers M, Phillips JJ, et al. Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta Neuropathol 2018;135:485-8.
-p
5. Goode B, Mondal G, Hyun M, et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 2018;9:810.
re
6. Rosenberg S, Simeonova I, Bielle F, et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat Commun 2018;9:2371.
lP
7. De jong MC, Kors WA, De graaf P, Castelijns JA, Kivelä T, Moll AC. Trilateral retinoblastoma: a systematic review and meta-analysis. Lancet Oncol 2014;15(10):1157-67.
ur
na
8. Gadish T, Tulchinsky H, Deutsch AA, Rabau M. Pinealoblastoma in a patient with familial adenomatous polyposis: variant of Turcot syndrome type 2? Report of a case and review of the literature. Dis Colon Rectum 2005;48:2343-6.
Jo
9. De kock L, Sabbaghian N, Druker H, et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol 2014;128:583-95. 10. Snuderl M, Kannan K, Pfaff E, et al. Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun 2018;9:2868. 11. Rakheja D, Chen KS, Liu Y, et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2014;2:4802. 12. Lee JC, Mazor T, Lao R, et al. Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma. Acta Neuropathol 2019;137:851-4. 13. Perry A, Scheithauer BW, Macaulay RJ, Raffel C, Roth KA, Kros JM. Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with diagnostic and histogenetic implications. J Neuropathol Exp Neurol 2002;61:947-55. 15
Journal Pre-proof
14. Sievers P, Stichel D, Schrimpf D, et al. FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathol 2018;136:293-302. 15. Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012;337:1231-5. 16. Lasorella A, Sanson M, Iavarone A. FGFR-TACC gene fusions in human glioma. Neurooncology 2017;19:475-483.
of
17. Rivera B, Gayden T, Carrot-zhang J, et al. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 2016;131:847-63.
ro
18. Qaddoumi I, Orisme W, Wen J, et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 2016;131:833-45.
re
-p
19. Sievers P, Appay R, Schrimpf D, et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol 2019 June 27 [Epub ahead of print].
na
lP
20. Huse JT, Snuderl M, Jones DT, et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 2017;133:417-429.
ur
21. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121:397-405.
Jo
22. Solomon DA, Korshunov A, Sill M, et al. Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNTlike methylation profile. Acta Neuropathol 2018;136:339-43. 23. Lucas CG, Villanueva-meyer JE, Whipple N, et al. Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. Brain Pathol 2019 October 14 [Epub ahead of print]. 24. Chiang JCH, Harreld JH, Tanaka R, et al. Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis. Neuro-oncology 2019;21:800-8. 25. Paugh BS, Zhu X, Qu C, et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 2013;73:6219-29.
16
Journal Pre-proof 26. Trabelsi S, Chabchoub I, Ksira I, et al. Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population. Mol Neurobiol 2017;54:2381-94. 27. Sturm D, Orr BA, Toprak UH, et al. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 2016;164:1060-72. 28. Meredith DM. Advances in Diagnostic Immunohistochemistry for Primary Tumors of the Central Nervous System. Adv Anat Pathol 2019 February 1 [Epub ahead of print].
of
29. Appay R, Macagno N, Padovani L, et al. HGNET-BCOR Tumors of the Cerebellum: Clinicopathologic and Molecular Characterization of 3 Cases. Am J Surg Pathol 2017;41:125460.
ro
30. Ferris SP, Velazquez vega J, Aboian M, et al. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol 2019 May 18 [Epub ahead of print].
re
-p
31. Yoshida Y, Nobusawa S, Nakata S, et al. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol 2018;28:710-20.
lP
32. Ueno-yokohata H, Okita H, Nakasato K, et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 2015;47:861-3.
ur
na
33. Kao YC, Sung YS, Zhang L, et al. Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 2016;40:1009-20.
Jo
34. Lehman NL, Hattab EM, Mobley BC, et al. Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults. Neuro-oncology 2017;19:31-42. 35. Hirose T, Nobusawa S, Sugiyama K, et al. Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement. Brain Pathol 2018;28:684-94. 36. Wood MD, Tihan T, Perry A, et al. Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol 2018;28:192202. 37. Lehman NL, Usubalieva A, Lin T, et al. Genomic analysis demonstrates that histologicallydefined astroblastomas are molecularly heterogeneous and that tumors with MN1 rearrangement exhibit the most favorable prognosis. Acta Neuropathol Commun 2019;7:42.
17
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9